Fabry syndrome is a multi-systemic, chromosome X-linked lysosomal storage disorder characterized by a reduction in alpha-galactosidase A activity, which leads to lysosomal deposition of neutralized glycosphingolipids & globotriaosylceramide GL-3. The usual skin lesion found in Fabry syndrome is angiokeratoma corporis diffusum, which is associated with renal dysfunction, particularly proteinuria.
Young adults who come with a cerebrovascular episode, myocardial infarction, & renal impairment should be evaluated for Fabry disease. With a greater tendency of the eye, skin, heart, kidney, brain, & peripheral nervous system, abnormalities in practically anywhere area of the human body might be identified.
Epidemiology
The prevalence of Fabry disease in white adult males ranges from roughly 1:17,000 – 1:117,000. Classical Fabry syndrome variants are seen in roughly 1:22,000 – 1:40,000 males, while atypical manifestations are found in approximately 1:1000 – 1:3000 males & 1:6000 – 1:40,000 females. Although being an underdiagnosed disorder, the disease affects people of all races & ethnicities.
Anatomy
Pathophysiology
The primary metabolic abnormality is a lack of lysosomal alpha-Gal A (alpha-galactosidase A). It is essential for the breakdown of (Gb3) globotriaosylceramide’s terminal galactose. It causes Gb3 to accumulate in a variety of tissues & cells, including the eye, skin, heart, kidney, brain, & peripheral nervous system. Vascular blockage, ischemia, & infarction can occur as a result of enhanced endothelial multiplication. The vertebrobasilar arteries are the most commonly affected by vascular dilatation, followed by minor cerebral vessels.
Young people with Fabry disease who have a stroke had low amounts of TM (thrombomodulin) & increased levels of PAI (plasminogen activator inhibitor), indicating that the condition is prothrombotic. Stroke mechanisms in juvenile Fabry illness have been connected to nitric oxide & non-nitric oxide-dependent endothelium proliferation & dilatation, as well as aberrant eNOS (endothelial nitric oxide synthase) activity.
Autonomic ganglia, Kidney glomerular, dorsal root ganglia, interstitial cells, tubular, cardiac muscle cells, valvular fibrocytes, vascular smooth muscle cells, cardiac conduction fibers, & the cornea are also common locations of Gb3 buildup. Gb3 deposition in the kidney is common, with deposits first appearing in the glomerulus, followed by the distal convoluted tubule. The propensity for Gb3 accumulation in these areas is linked to the onset of early polyuria & proteinuria. The mechanism underlying the production of renal sinus cysts in Fabry syndrome is unknown.
Etiology
Hundreds of variants in the alpha-Gal A gene on the X chromosome have been confirmed to cause Fabry’s disease. The principal reason for lysosomal glycosphingolipid accumulation, specifically the cerebroside trihexosides, is a lack of alpha-Gal A.
Progressive glycolipid buildup, which causes swelling & endothelial cell proliferation, leads to kidney failure in the third to fourth decades, as well as cardiac illness, strokes, & premature mortality.
These mutations are related to the classic Fabry phenotype, which manifests as multisystem interaction. Milder types caused by missense alterations are characterized by cardiac problems.
Genetics
Prognostic Factors
Following a first stroke, an individual is at high risk of having another. Heterozygous females have substantially weaker symptoms than heterozygous men.
Clinical History
Clinical history
The typical clinical features of Fabry disease include:
Pain: This is one of the most common symptoms of Fabry disease and usually affects the hands and feet. The pain can be triggered by physical activity, heat, or cold.
Skin manifestations: The skin can be affected in several ways, including angiokeratomas, small raised lesions that appear on the skin, and hypohidrosis, a reduced ability to sweat.
Gastrointestinal symptoms: Patients with Fabry disease may experience abdominal pain, diarrhea, constipation, and nausea.
Renal dysfunction: Fabry disease can lead to kidney damage, which can progress to kidney failure. This can be detected by proteinuria, an excessive amount of protein in the urine.
Cardiovascular disease: Fabry disease can also cause heart disease, including left ventricular hypertrophy, arrhythmias, and myocardial infarction.
Other symptoms of Fabry disease may include hearing loss, tinnitus, vertigo, visual impairment, and cerebrovascular disease. The severity and progression of Fabry’s disease can vary widely, even among members of the same family.
Fabry disease can be diagnosed through genetic testing and enzyme activity testing. Treatment options include enzyme replacement therapy, which replaces the missing enzyme in the body, and symptomatic treatment for pain and other symptoms.
Physical Examination
Physical examination
During a physical examination of a patient with Fabry disease, the following findings may be observed:
Skin: Small, dark red, raised bumps called angiokeratomas may be present on the skin, particularly in the groin and lower abdomen. The skin may also appear dry and scaly, and there may be areas of decreased sweating.
Eyes: The eyes may show signs of corneal opacity, which can impair vision.
Hearing: Hearing loss or tinnitus may be present.
Heart: Cardiac examination may reveal a loud S4 heart sound, indicating decreased compliance of the left ventricle. There may also be evidence of left ventricular hypertrophy, arrhythmias, or other signs of cardiovascular disease.
Kidneys: A thorough examination of the kidneys may reveal signs of renal dysfunction, such as proteinuria and decreased kidney function.
Neurological system: Neurological examination may reveal signs of cerebrovascular disease, such as weakness or numbness in the extremities, or signs of peripheral neuropathy, such as decreased sensation in the feet.
Overall, a physical examination in patients with Fabry disease may reveal a range of symptoms and signs that vary depending on the severity and progression of the disease. Diagnosis and management of Fabry disease typically involve a multidisciplinary approach, including medical genetics, cardiology, nephrology, and neurology.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential diagnosis
Multiple sclerosis
Lacunar syndromes
Cavernous sinus syndromes
Stroke
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
This condition cannot be healed fully. In affected individuals & patients on kidney transplantation, the primary supportive therapy for Fabry syndrome is to substitute the defective enzyme alpha-galactosidase A (alpha and beta) as soon as the identification is made, despite the existence or lack of clinical symptoms. Female carriers & infected males with low Alpha-Gal A levels should receive enzyme replenishment only if they have renal, cardiac, and neurological symptoms.
Long-term dialysis patients should additionally obtain enzyme replacement treatment. Angiotensin-converting enzyme blockers and blockers of angiotensin receptors should be used to treat hypertension in those patients. According to body composition estimations, enzyme alpha, and beta replacement injections should be administered every 2 weeks.
Infusion-related responses should be avoided at all costs. Slow administration over 1 to 2 hours, with antipyretics administered beforehand, might be considered. End-stage renal illness individuals with Fabry syndrome can be considered for kidney transplantation with ongoing enzyme replacement post-transplant.
Pre-treatment
Patients with prior exposure to enzyme replacement treatment(ERT)
Suppose antihistamines, fever reducers, and corticosteroids were used before ERT. In that case, you use them again before the first few pegunigalsidase injections.
If tolerated after 4–6 infusions, consider reducing the dose(s) of pretreatment medications or discontinuing.
ERT-naive patients
pegunigalsidase alfa infusion may be preceded by using antihistamines, antipyretics, or corticosteroids.
Dose Adjustments
Infusion-associated responses (IAR) or hypersensitivity
Mild-to-moderate
Consider pausing the infusion for 15 to 30 minutes, reducing the infusion rate by 25 to 50%, and initiating the appropriate medical treatment.
If symptoms continue despite holding or reducing the infusion, stop it and monitor things. You could think about starting it again in 7–14 days with a 25–50% slower infusion rate.
Restart the infusion if the symptoms disappear after stopping it, then reduce the rate by 25–50% as tolerated.
Up to the infusion rate at which the response occurred, start with the subsequent infusion and gradually raise the infusion rate by 25% increments every third infusion as tolerated.
Severe
Stop the injection immediately and start the proper medical care
Hepatic or Renal Impairment
No dosage modification needed
It is indicated for adults diagnosed with Fabry disease and amenable GLA (galactosidase alpha gene) variant in vitro data
123 mg orally once on alternate days at the same time of the day
No dose adjustment is required in the case of mild to moderate renal impairment
But it is not recommended when severe end-to-end renal disease persists
Fabry syndrome is a multi-systemic, chromosome X-linked lysosomal storage disorder characterized by a reduction in alpha-galactosidase A activity, which leads to lysosomal deposition of neutralized glycosphingolipids & globotriaosylceramide GL-3. The usual skin lesion found in Fabry syndrome is angiokeratoma corporis diffusum, which is associated with renal dysfunction, particularly proteinuria.
Young adults who come with a cerebrovascular episode, myocardial infarction, & renal impairment should be evaluated for Fabry disease. With a greater tendency of the eye, skin, heart, kidney, brain, & peripheral nervous system, abnormalities in practically anywhere area of the human body might be identified.
The prevalence of Fabry disease in white adult males ranges from roughly 1:17,000 – 1:117,000. Classical Fabry syndrome variants are seen in roughly 1:22,000 – 1:40,000 males, while atypical manifestations are found in approximately 1:1000 – 1:3000 males & 1:6000 – 1:40,000 females. Although being an underdiagnosed disorder, the disease affects people of all races & ethnicities.
The primary metabolic abnormality is a lack of lysosomal alpha-Gal A (alpha-galactosidase A). It is essential for the breakdown of (Gb3) globotriaosylceramide’s terminal galactose. It causes Gb3 to accumulate in a variety of tissues & cells, including the eye, skin, heart, kidney, brain, & peripheral nervous system. Vascular blockage, ischemia, & infarction can occur as a result of enhanced endothelial multiplication. The vertebrobasilar arteries are the most commonly affected by vascular dilatation, followed by minor cerebral vessels.
Young people with Fabry disease who have a stroke had low amounts of TM (thrombomodulin) & increased levels of PAI (plasminogen activator inhibitor), indicating that the condition is prothrombotic. Stroke mechanisms in juvenile Fabry illness have been connected to nitric oxide & non-nitric oxide-dependent endothelium proliferation & dilatation, as well as aberrant eNOS (endothelial nitric oxide synthase) activity.
Autonomic ganglia, Kidney glomerular, dorsal root ganglia, interstitial cells, tubular, cardiac muscle cells, valvular fibrocytes, vascular smooth muscle cells, cardiac conduction fibers, & the cornea are also common locations of Gb3 buildup. Gb3 deposition in the kidney is common, with deposits first appearing in the glomerulus, followed by the distal convoluted tubule. The propensity for Gb3 accumulation in these areas is linked to the onset of early polyuria & proteinuria. The mechanism underlying the production of renal sinus cysts in Fabry syndrome is unknown.
Hundreds of variants in the alpha-Gal A gene on the X chromosome have been confirmed to cause Fabry’s disease. The principal reason for lysosomal glycosphingolipid accumulation, specifically the cerebroside trihexosides, is a lack of alpha-Gal A.
Progressive glycolipid buildup, which causes swelling & endothelial cell proliferation, leads to kidney failure in the third to fourth decades, as well as cardiac illness, strokes, & premature mortality.
These mutations are related to the classic Fabry phenotype, which manifests as multisystem interaction. Milder types caused by missense alterations are characterized by cardiac problems.
Following a first stroke, an individual is at high risk of having another. Heterozygous females have substantially weaker symptoms than heterozygous men.
Clinical history
The typical clinical features of Fabry disease include:
Pain: This is one of the most common symptoms of Fabry disease and usually affects the hands and feet. The pain can be triggered by physical activity, heat, or cold.
Skin manifestations: The skin can be affected in several ways, including angiokeratomas, small raised lesions that appear on the skin, and hypohidrosis, a reduced ability to sweat.
Gastrointestinal symptoms: Patients with Fabry disease may experience abdominal pain, diarrhea, constipation, and nausea.
Renal dysfunction: Fabry disease can lead to kidney damage, which can progress to kidney failure. This can be detected by proteinuria, an excessive amount of protein in the urine.
Cardiovascular disease: Fabry disease can also cause heart disease, including left ventricular hypertrophy, arrhythmias, and myocardial infarction.
Other symptoms of Fabry disease may include hearing loss, tinnitus, vertigo, visual impairment, and cerebrovascular disease. The severity and progression of Fabry’s disease can vary widely, even among members of the same family.
Fabry disease can be diagnosed through genetic testing and enzyme activity testing. Treatment options include enzyme replacement therapy, which replaces the missing enzyme in the body, and symptomatic treatment for pain and other symptoms.
Physical examination
During a physical examination of a patient with Fabry disease, the following findings may be observed:
Skin: Small, dark red, raised bumps called angiokeratomas may be present on the skin, particularly in the groin and lower abdomen. The skin may also appear dry and scaly, and there may be areas of decreased sweating.
Eyes: The eyes may show signs of corneal opacity, which can impair vision.
Hearing: Hearing loss or tinnitus may be present.
Heart: Cardiac examination may reveal a loud S4 heart sound, indicating decreased compliance of the left ventricle. There may also be evidence of left ventricular hypertrophy, arrhythmias, or other signs of cardiovascular disease.
Kidneys: A thorough examination of the kidneys may reveal signs of renal dysfunction, such as proteinuria and decreased kidney function.
Neurological system: Neurological examination may reveal signs of cerebrovascular disease, such as weakness or numbness in the extremities, or signs of peripheral neuropathy, such as decreased sensation in the feet.
Overall, a physical examination in patients with Fabry disease may reveal a range of symptoms and signs that vary depending on the severity and progression of the disease. Diagnosis and management of Fabry disease typically involve a multidisciplinary approach, including medical genetics, cardiology, nephrology, and neurology.
Differential diagnosis
Multiple sclerosis
Lacunar syndromes
Cavernous sinus syndromes
Stroke
This condition cannot be healed fully. In affected individuals & patients on kidney transplantation, the primary supportive therapy for Fabry syndrome is to substitute the defective enzyme alpha-galactosidase A (alpha and beta) as soon as the identification is made, despite the existence or lack of clinical symptoms. Female carriers & infected males with low Alpha-Gal A levels should receive enzyme replenishment only if they have renal, cardiac, and neurological symptoms.
Long-term dialysis patients should additionally obtain enzyme replacement treatment. Angiotensin-converting enzyme blockers and blockers of angiotensin receptors should be used to treat hypertension in those patients. According to body composition estimations, enzyme alpha, and beta replacement injections should be administered every 2 weeks.
Infusion-related responses should be avoided at all costs. Slow administration over 1 to 2 hours, with antipyretics administered beforehand, might be considered. End-stage renal illness individuals with Fabry syndrome can be considered for kidney transplantation with ongoing enzyme replacement post-transplant.
https://www.ncbi.nlm.nih.gov/books/NBK435996/
medtigo
Fabry Disease
Updated :
January 8, 2024
Fabry syndrome is a multi-systemic, chromosome X-linked lysosomal storage disorder characterized by a reduction in alpha-galactosidase A activity, which leads to lysosomal deposition of neutralized glycosphingolipids & globotriaosylceramide GL-3. The usual skin lesion found in Fabry syndrome is angiokeratoma corporis diffusum, which is associated with renal dysfunction, particularly proteinuria.
Young adults who come with a cerebrovascular episode, myocardial infarction, & renal impairment should be evaluated for Fabry disease. With a greater tendency of the eye, skin, heart, kidney, brain, & peripheral nervous system, abnormalities in practically anywhere area of the human body might be identified.
The prevalence of Fabry disease in white adult males ranges from roughly 1:17,000 – 1:117,000. Classical Fabry syndrome variants are seen in roughly 1:22,000 – 1:40,000 males, while atypical manifestations are found in approximately 1:1000 – 1:3000 males & 1:6000 – 1:40,000 females. Although being an underdiagnosed disorder, the disease affects people of all races & ethnicities.
The primary metabolic abnormality is a lack of lysosomal alpha-Gal A (alpha-galactosidase A). It is essential for the breakdown of (Gb3) globotriaosylceramide’s terminal galactose. It causes Gb3 to accumulate in a variety of tissues & cells, including the eye, skin, heart, kidney, brain, & peripheral nervous system. Vascular blockage, ischemia, & infarction can occur as a result of enhanced endothelial multiplication. The vertebrobasilar arteries are the most commonly affected by vascular dilatation, followed by minor cerebral vessels.
Young people with Fabry disease who have a stroke had low amounts of TM (thrombomodulin) & increased levels of PAI (plasminogen activator inhibitor), indicating that the condition is prothrombotic. Stroke mechanisms in juvenile Fabry illness have been connected to nitric oxide & non-nitric oxide-dependent endothelium proliferation & dilatation, as well as aberrant eNOS (endothelial nitric oxide synthase) activity.
Autonomic ganglia, Kidney glomerular, dorsal root ganglia, interstitial cells, tubular, cardiac muscle cells, valvular fibrocytes, vascular smooth muscle cells, cardiac conduction fibers, & the cornea are also common locations of Gb3 buildup. Gb3 deposition in the kidney is common, with deposits first appearing in the glomerulus, followed by the distal convoluted tubule. The propensity for Gb3 accumulation in these areas is linked to the onset of early polyuria & proteinuria. The mechanism underlying the production of renal sinus cysts in Fabry syndrome is unknown.
Hundreds of variants in the alpha-Gal A gene on the X chromosome have been confirmed to cause Fabry’s disease. The principal reason for lysosomal glycosphingolipid accumulation, specifically the cerebroside trihexosides, is a lack of alpha-Gal A.
Progressive glycolipid buildup, which causes swelling & endothelial cell proliferation, leads to kidney failure in the third to fourth decades, as well as cardiac illness, strokes, & premature mortality.
These mutations are related to the classic Fabry phenotype, which manifests as multisystem interaction. Milder types caused by missense alterations are characterized by cardiac problems.
Following a first stroke, an individual is at high risk of having another. Heterozygous females have substantially weaker symptoms than heterozygous men.
Clinical history
The typical clinical features of Fabry disease include:
Pain: This is one of the most common symptoms of Fabry disease and usually affects the hands and feet. The pain can be triggered by physical activity, heat, or cold.
Skin manifestations: The skin can be affected in several ways, including angiokeratomas, small raised lesions that appear on the skin, and hypohidrosis, a reduced ability to sweat.
Gastrointestinal symptoms: Patients with Fabry disease may experience abdominal pain, diarrhea, constipation, and nausea.
Renal dysfunction: Fabry disease can lead to kidney damage, which can progress to kidney failure. This can be detected by proteinuria, an excessive amount of protein in the urine.
Cardiovascular disease: Fabry disease can also cause heart disease, including left ventricular hypertrophy, arrhythmias, and myocardial infarction.
Other symptoms of Fabry disease may include hearing loss, tinnitus, vertigo, visual impairment, and cerebrovascular disease. The severity and progression of Fabry’s disease can vary widely, even among members of the same family.
Fabry disease can be diagnosed through genetic testing and enzyme activity testing. Treatment options include enzyme replacement therapy, which replaces the missing enzyme in the body, and symptomatic treatment for pain and other symptoms.
Physical examination
During a physical examination of a patient with Fabry disease, the following findings may be observed:
Skin: Small, dark red, raised bumps called angiokeratomas may be present on the skin, particularly in the groin and lower abdomen. The skin may also appear dry and scaly, and there may be areas of decreased sweating.
Eyes: The eyes may show signs of corneal opacity, which can impair vision.
Hearing: Hearing loss or tinnitus may be present.
Heart: Cardiac examination may reveal a loud S4 heart sound, indicating decreased compliance of the left ventricle. There may also be evidence of left ventricular hypertrophy, arrhythmias, or other signs of cardiovascular disease.
Kidneys: A thorough examination of the kidneys may reveal signs of renal dysfunction, such as proteinuria and decreased kidney function.
Neurological system: Neurological examination may reveal signs of cerebrovascular disease, such as weakness or numbness in the extremities, or signs of peripheral neuropathy, such as decreased sensation in the feet.
Overall, a physical examination in patients with Fabry disease may reveal a range of symptoms and signs that vary depending on the severity and progression of the disease. Diagnosis and management of Fabry disease typically involve a multidisciplinary approach, including medical genetics, cardiology, nephrology, and neurology.
Differential diagnosis
Multiple sclerosis
Lacunar syndromes
Cavernous sinus syndromes
Stroke
This condition cannot be healed fully. In affected individuals & patients on kidney transplantation, the primary supportive therapy for Fabry syndrome is to substitute the defective enzyme alpha-galactosidase A (alpha and beta) as soon as the identification is made, despite the existence or lack of clinical symptoms. Female carriers & infected males with low Alpha-Gal A levels should receive enzyme replenishment only if they have renal, cardiac, and neurological symptoms.
Long-term dialysis patients should additionally obtain enzyme replacement treatment. Angiotensin-converting enzyme blockers and blockers of angiotensin receptors should be used to treat hypertension in those patients. According to body composition estimations, enzyme alpha, and beta replacement injections should be administered every 2 weeks.
Infusion-related responses should be avoided at all costs. Slow administration over 1 to 2 hours, with antipyretics administered beforehand, might be considered. End-stage renal illness individuals with Fabry syndrome can be considered for kidney transplantation with ongoing enzyme replacement post-transplant.
https://www.ncbi.nlm.nih.gov/books/NBK435996/
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